Department of Pharmacology, University of Oxford, Oxford, UK.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Life Sci Alliance. 2020 Jun 2;3(7). doi: 10.26508/lsa.201800253. Print 2020 Jul.
Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the or genes. Mutations in the gene lead to the majority of clinical cases (95%); however, the function of NPC1 remains unknown. To gain further insights into the biology of NPC1, we took advantage of the homology between the human NPC1 protein and its yeast orthologue, Niemann-Pick C-related protein 1 (Ncr1). We recreated the mutant in yeast and performed screens to identify compensatory or redundant pathways that may be involved in NPC pathology, as well as proteins that were mislocalized in -deficient yeast. We also identified binding partners of the yeast Ncr1 orthologue. These screens identified several processes and pathways that may contribute to NPC pathogenesis. These included alterations in mitochondrial function, cytoskeleton organization, metal ion homeostasis, lipid trafficking, calcium signalling, and nutrient sensing. The mitochondrial and cytoskeletal abnormalities were validated in patient cells carrying mutations in , confirming their dysfunction in NPC disease.
尼曼-匹克病 C 型（NPC）是一种罕见的溶酶体贮积病，由 或 基因的突变引起。 基因突变导致大多数临床病例（95%）；然而，NPC1 的功能仍然未知。为了更深入地了解 NPC1 的生物学特性，我们利用人类 NPC1 蛋白与其酵母同源物尼曼-匹克 C 相关蛋白 1（Ncr1）之间的同源性。我们在酵母中重新构建了 突变体，并进行了筛选，以鉴定可能参与 NPC 病理的补偿或冗余途径，以及在 NPC1 缺陷酵母中定位错误的蛋白质。我们还鉴定了酵母 Ncr1 同源物的结合伙伴。这些筛选确定了几个可能导致 NPC 发病机制的过程和途径。这些包括线粒体功能、细胞骨架组织、金属离子动态平衡、脂质运输、钙信号转导和营养感应的改变。在携带 基因突变的患者细胞中验证了线粒体和细胞骨架异常，证实了它们在 NPC 疾病中的功能障碍。
